New therapies for malaria are urgently needed. Combination therapy for uncomplicated malaria appears to offer the best opportunity for effective therapy and for the prevention of selection of resistant parasites. However, it is not clear how best to compare the efficacies of antimalarial regimens. Recent results from our group and others suggest that traditional short-term evaluations of efficacy are not adequate to most appropriately compare different regimens. Rather, important differences may only be apparent after long-term evaluation. Longitudinal evaluation also provides a "real world" comparison of different regimens, with assessments of the effects of repeated dosing on malarial incidence, selection of resistant parasites, and drug toxicity. New molecular techniques allow improvements in longitudinal studies, by providing accurate assessment of treatment responses. They can also help to characterize the roles of parasite and host polymorphisms in disease incidence and responses to therapy. We hypothesize that longitudinal evaluation will identify important differences between the efficacies and selective pressures of leading antimalarial combination therapies; even if short-term activities are similar. We further hypothesize that identifiable parasite and host polymorphisms will help predict outcomes after antimalarial therapy and that the characterization of these polymorphisms will identify factors that contribute to responses to therapy. This project is designed to test these hypotheses through a longitudinal comparison of four combination therapies for uncomplicated malaria and the performance of related molecular studies to characterize the parasite and host factors that impact upon disease. The project will include clinical studies at our study site in Kampala, Uganda and related biochemistry and molecular studies in Kampala and San Francisco. Our specific aims will be (1) to compare the efficacies of combination antimalarial therapies using a longitudinal design, (2) to follow plasmodia genetic polymorphisms as longitudinal markers of antimalarial drug resistance, and (3) to evaluate the roles of host genetic polymorphisms in antimalarial drug resistance and the incidence of clinical malaria. We anticipate that the experiments designed to achieve these aims will contribute to improved management of malaria and to a better understanding of the genetic factors that impact upon responses to therapy for this disease. [unreadable] [unreadable]